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PET imaging of beta-adrenoceptors in human brain: A realistic goal or a mirage? van Waarde, Aaren; Vaalburg, W.; Doze, Petra; Bosker, Fokko; Elsinga, P.H

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Citation for published version (APA): van Waarde, A., Vaalburg, W., Doze, P., Bosker, F., & Elsinga, P. H. (2004). PET imaging of beta- adrenoceptors in human brain: A realistic goal or a mirage? Current Pharmaceutical Design, 10(13), 1519 - 1536.

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Download date: 03-10-2021 Current Pharmaceutical Design, 2004, 10, 1519-1536 1519 PET Imaging of Beta-Adrenoceptors in Human Brain: A Realistic Goal or a Mirage?

Aren van Waarde*, Willem Vaalburg, Petra Doze, Fokko J.Bosker1 and Philip H. Elsinga

PET Center and 1Dept. Biological Psychiatry, Groningen University Hospital P.O.Box 30001, Hanzeplein 1 9700 RB Groningen The Netherlands

Abstract: Beta-adrenoceptors are predominantly located in the cerebral cortex, nucleus accumbens and striatum. At lower densities, they are also present in amygdala, hippocampus and cerebellum. Beta-2 sites regulate glial proliferation during ontogenic development, after trauma and in neurodegenerative diseases. The densities of beta-1 adrenoceptors are changed by stress, in several mood disorders (depression, excessive hostility, schizophrenia) and during treatment of patients with antidepressants. A technique for beta-adrenoceptor imaging in the human brain is not yet available. Although 24 (ant)agonists have been labeled with either 11C or 18F and some of these are successful myocardial imaging agents, only two (S-1’-18F- fluorocarazolol and S-1’-18F-fluoroethylcarazolol) could actually visualize ß-adrenoceptors within the central nervous system. Unfortunately, these radiopharmaceuticals showed a positive Ames test. They may be mutagenic and cannot be employed for human studies. Screening of more than 150 beta-blockers described in the literature yields only two compounds (exaprolol and L643,717) which can still be radiolabeled and evaluated for ß-adenoceptor imaging. However, other imaging techniques could be examined. Cerebral ß-adrenoceptors might be labeled after temporary opening of the blood-brain barrier (BBB) and simultaneous administration of a hydrophilic ligand such as S-11C-CGP12388. Another approach to target ß-adrenoceptor ligands to the CNS is esterification of a myocardial imaging agent (such as 11C-CGP12177), resulting in a lipophilic prodrug which can cross the BBB and is split by tissue esterases. BBB opening is not feasible in healthy subjects, but the prodrug approach may be successful and deserves to be explored. Key Words: Beta-adrenoceptors, positron emission tomography, human, brain, depression, multiple sclerosis, radiopharma- ceuticals, imaging.

INTRODUCTION in the first decade of the twentieth century [51]. Later, it was In the autonomic nervous system, two networks can be shown that the adrenoceptor family could be divided in two distinguished which regulate the internal environment to populations, called a - and b-adrenoceptors [8]. The former maintain a steady-state (homeostasis): the sympathetic and induce activation of the uterus and vasoconstriction, the latter inhibition of the uterus and vasodilation. Later still, ß- the parasympathetic system. The latter network maintains basal functions (heart rate, respiration, etc.) under normal adrenoceptors were classified in two different subtypes: ß1 conditions, whereas the former responds to threatening situa- and ß2 [136]. Beta-1 agonists stimulate cardiac contractility and lipolysis, whereas beta-2 agonists cause bronchodilation tions (hypoglycemia, hypoxia, sudden changes in the environ- ment). Sympathetic activation results e.g. in increased and vasodepression. Since then, ß1-adrenoceptors involved in cardiac output, body temperature and blood glucose in order lipolysis have been reclassified as ‘atypical’ or ß3-adreno- to respond adequately in case of an emergency. ceptors [14]. A fourth subtype, the putative ß4-adrenoceptor, has been suggested to exist in myocardial and adipose tissue The physiological responses resulting from activation of [84, 127]. Blocking this subtype requires much higher the sympathetic nervous system are mediated by the neuro- concentrations of ß-adrenoceptor antagonists than those transmitter noradrenalin and the hormone adrenalin. These required to block ß1- or ß2-adrenoceptors. catecholamines originate from the amino acid tyrosine. Since responses to stressful situations occur all over the Noradrenalin is synthesized in nerve endings, while adrena- body, ß-adrenoceptors are present in many different organs. lin is produced mainly in the chromaffin cells of the adrenal Stimulation of myocardial receptors increases heart rate and medulla. Both compounds activate specific membrane recep- contractile force, resulting in enhanced cardiac output [32]. tors called adrenoceptors. The interaction of noradrenalin Stimulation of pulmonary ß-adrenoceptors causes bronchodi- with these receptors was discovered by Sir Henry Dale lation and increased blood flow, resulting in enhanced oxygen uptake [16]. Beta-adrenoceptors in the pancreas regulate the secretion of glucagon [135], while those in the *Address correspondence to this author at the PET Center, Groningen University Hospital, P.O. Box 30001, Hanzeplein 1, 9700 RB Groningen, liver and kidney control glycogenolysis and glucose release The Netherlands; Tel: +31-50-3613215; Fax: +31-50-3611687; [125, 91]. The overall effect of stimulation of these receptors E-mail: [email protected] is an increased availability of glucose and an increased

1381-6128/04 $45.00+.00 © 2004 Bentham Science Publishers Ltd. 1520 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al. capacity of tissues to use glucose as a fuel. Beta-adreno- interpret because of the heterogeneity of the patient groups ceptors in the spleen are involved in the stress-induced (e.g., large differences in medication) and the fact that many augmentation of circulatory blood volume and lymphoid cell different radioligands were used in the receptor assays. Later mobilization [232, 196]. The secretion of many glands, studies employing more stringent inclusion criteria demons- including the lacrimal [1], salivary [188], thyroid [9] and trated ß-adrenoceptor decreases in several cortical areas, not pituitary [210] glands, is also under ß-adrenergic control. only in antidepressant-treated but also in drug-free depressed Physiological and behavioral responses to noradrenalin in patients [55, 149, 202]. After long-term treatment with the central nervous system are regulated predominantly by antidepressants, cerebral ß-adrenoceptors are downregulated two different nuclei in the brain stem: the locus coeruleus in human brain [56, 11]. and the lateral tegmental neurons. The former has very broad Several other disorders of mood and behavior, such as projections throughout the brain. Much less noradrenergic schizophrenia [130, 121], excessive hostility [256, 222], neurons project from the lateral tegmental neurons to the premenstrual dysphoria [95] and chronic alcohol abuse [94] brain stem, spinal cord and thalamus. While the lateral have been reported to be accompanied by abnormal ß- tegmental neurons contribute to the integration of autonomic adrenoceptor densities and/or coupling of ß-adrenoceptors to functions (blood pressure and heart rate), the projections of the Gs protein. Low doses of lipophilic ß-blockers proved the locus coeruleus play an important role in behavioral often effective in the suppression of psychosis or anxiety and responses such as orientation, and reactions to sudden the reduction of aggressive behavior in chronic psychiatric contrasting or aversive sensori stimuli [167]. patients [96, 15, 75]. Cerebral ß-adrenoceptors are involved in several physio- Neurodegenerative diseases may also be associated with logical functions, such as respiratory [12, 81], cardiovascular abnormal ß-adrenoceptor function. In some patients with [231] and renal [132] sympathetic nervous control. Further- Parkinson’s disease, an increased number of ß1 adrenocep- more, ß-adrenoceptors located on glial cells regulate (injury- tors was found in the pre-frontal cortex [38]. Alzheimer’s induced) astrogliosis and microglial proliferation [224, 85, dementia has been reported to be accompanied by changes of 104, 83]. These processes contribute to neuronal regenera- the relative sizes of ß-adrenoceptor subpopulations (decrease tion after injury, but they can also play a negative role in of ß1, increase of ß2) [123, 247] and impaired ß-adrenoceptor neurodegenerative diseases and contribute to ischemia- coupling to adenylyl cyclase [47] in various regions of the induced neuronal death [116, 154]. Biological rhythms, such brain. An almost complete loss of ß1-adrenoceptors in basal as the diurnal activity cycle [251, 122], the sleep/wakeful- ganglia of patients suffering from Huntington’s disease is ness cycle [217] and annual hibernation [182] are accom- observed only in late stages of the disease. This loss is panied by changes of ß-adrenoceptor density and/or ß- accompanied by a strong increase of ß2-adrenoceptor density adrenoceptor signalling in particular brain areas. in the posterior putamen, probably as a result of gliosis Cerebral ß-adrenoceptors are essential to various memory [249]. Normal aging is accompanied by a slow decrease of functions, such as memory storage of emotional events [159, ß1-adrenoceptor densities in human brain [123, 202]. Apparently, this loss is accelerated in certain forms of 36], motor learning [102], conditioned olfactory [145] and taste [20] learning. They also regulate the processing of neurodegeneration. visual information [170]. Memory functions, processing of external information and the ability to hibernate are required POSITRON EMISSION TOMOGRAPHY (PET) OF to respond correctly in case of emergencies. CEREBRAL ß-ADRENOCEPTORS Studies in rodents have revealed changes of regional ß- If a method could be developed to image and quantify ß- adrenoceptor density and of the activity of ß-adrenoceptor- adrenoceptors in the human brain, this would allow investi- coupled second messenger systems after exposure of the gators to answer several questions: animals to stress. Acute or unpredictable stress is thought to (a) Beta-adrenoceptor occupancy of novel and existing be accompanied by an increase of ß-adrenoceptor density, CNS drugs could be measured and related to plasma probably in order to assess the danger of a situation [179]. In levels of the drug , to the desired therapeutic effect and contrast, a predictable form of chronic stress is often to undesired side effects. accompanied by a reduction of ß-adrenoceptor numbers [80, (b) Changes in after adminis- 103]. This reduction may be interpreted as an adaptation of ß-adrenoceptor availability the animal to recurrent stressful events and the accompany- tration of noradrenalin reuptake inhibitors could be assessed in the intact human brain, reduced ß-adreno- ing release of large amounts of catecholamines. In some ceptor availability indicating increased occupancy of studies, there were no changes of ß-adrenoceptor density after exposure of animals to stress [29, 93, 100]. These the ß-adrenoceptor population by endogenous noradre- nalin. conflicting results may be due to the different stress paradi- gms and test procedures that were employed. (c) The time course of ß1-adrenoceptor downregulation in patients during treatment with antidepressants could Postmortem studies in humans have provided evidence for abnormal ß-adrenoceptor density and function in mood then be assessed and related to mood changes in the disorders such as depression. Initial studies in suicide victims same subjects. reported either increases [13, 23], no alteration [162, 221, (d) It would become possible to make a differential diagno- 48], or decreases [54] in various brain areas, such as the sis between multiple sclerosis and other neurodegenera- frontal cortex and hippocampus. The data were difficult to tive diseases in an early stage of the disease. White PET Imaging of Beta-Adrenoceptors in Human Brain Current Pharmaceutical Design, 2004, Vol. 10, No. 13 1521

matter in the brain of healthy subjects is virtually CRITERIA FOR THE SELECTION OF LIGAND devoid of ß-adrenergic sites [257], but glial cells poss- CANDIDATES ess ß -adrenoceptors [154]. Gliosis after neurodegenera- 2 1. Affinity tion might therefore be visualized with a suitable ß2- adrenoceptor ligand and PET. Proliferation of microglia Receptor imaging requires a specific signal above results normally in increased ß2-adrenoceptor densities background radioactivity. To predict if a radioligand will in white matter, but astrocyte proliferation in multipe provide a specific signal that can be detected externally, the sclerosis is not accompanied by such increases because bound/free ratio (B/F) is often estimated from the Scatchard astrocytes in MS have lost their ß2-adrenoceptors [52, equation [205]: 257]. B/F = Bmax/Kd - B/Kd Myocardial and pulmonary ß-adrenoceptors in patients Since the specific activity of positron-emitting radio- and healthy volunteers have already been quantified, using ligands is very high (i.e., B is very small), the term B/K can the radiolabeled antagonists S-11C-CGP12177 [98, 139, 161, d 11 be neglected and B/F is approximately equal to Bmax/Kd. This 185, 186, 206, 239] and S- C-CGP12388 [64, 72]. Since the ratio, originating from equilibrium binding equations devel- lipophilicity of these radiopharmaceuticals is very low 1 oped for in vitro binding assays, describes target/nontarget (calculated log P at pH 7.4 -2.07 and -2.01, respectively ), binding in the ideal case. The actual ratio of bound/free they do not cross the blood-brain barrier. Therefore, the radioactivity observed in vivo is often much lower because of Ciba-Geigy compounds are not suitable for visualization of metabolism, protein binding and non-specific uptake of the ß-adrenoceptors in the central nervous system. radioligand [86]. For receptor visualisation, a B/F ratio ³ 10 Some lipophilic ß-adrenoceptor antagonists have also is required in planar imaging and ³ 4 in PET [88, 70]. 11 been labeled with a positron emitter. These include: S- C- Estimations of ß-adrenoceptor density (B ) in human bisoprolol (logP -0.20, [215]), S-11C-carazolol (logP +0.80, max 11 18 brain vary over a fairly wide range depending on the [21]), C-carvedilol (logP +2.97, [63]), S- F-fluorocara- laboratory of assay, the radioligand employed, the method zolol (logP +2.19, [258]), S-18F-fluoroethylcarazolol (logP 18 used to obtain a membrane fraction and the age and personal +1.66, [67]), F-fluoroisopropylbupranolol (logP +1.93, history of the subjects. In frontal cortex, the lowest value [63]), 18F-fluoroisopropylpenbutolol (logP +2.53, [63]), 18F- 11 reported was 18 fmol/mg protein [38] and the highest value fluoropropranolol (logP +1.81, [234]), C-ICI 118,551 (logP was 147 fmol/mg protein [209]. If we assume an average +1.07, [168]), 11C-pindolol (logP -0.53, [184]), 11C-propra- 11 protein content of tissue of 10%, these values correspond to nolol (logP +0.43, [19]) and C-toliprolol (logP -0.22, [63]). 1.8-14.7 pmol/g wet weight. Thus, the affinity of a radio- Only two out of these twelve radiopharmaceuticals displayed 18 18 ligand to visualize ß-adrenoceptors in the frontal cortex specific binding in rodent brain: F-fluorocarazolol and F- should be < 0.45-3.7 nM for PET (B /K >4) and < 0.18- fluoroethylcarazolol. A pilot study with non-carrier-added max d 18 1.47 nM for planar imaging (Bmax/Kd >10). In reality, the F-fluorocarazolol indicated specific binding of this affinity should be even higher because there is always some radioligand also in the human brain [243]. Unfortunately, in metabolism, protein and non-specific binding. later more extensive screening, both fluorinated carazolol analogs showed a positive Ames (i.e., mutagenicity) test 2. Lipophilicity ([62], Doze unpublished). Therefore, these radioligands can no longer be employed for human studies. Imaging of neuroreceptors within the CNS is only possible when the radiopharmaceutical is transported across Radioiodinated analogs of pindolol (ICYP and IPIN) the blood-brain barrier (BBB). The cerebral endothelium acts display some specific binding within the CNS in vivo [236, as a lipophilic physical barrier by which the passive entry of 63], but the brain uptake of these compounds is low, result- hydrophilic compounds into the brain is restricted. Optimal ing in very poor signal-to-noise ratios. Moreover, ICYP binds diffusion across the blood-brain barrier occurs if the drug has not only to ß-adrenoceptors, but also to several subtypes of an octanol/water partition coefficient (log P) of +2 to +3, the the serotonin (5-HT) receptor within the brain [63]. maximum of the parabola describing the relationship Since no other radiopharmaceuticals are available for between lipophilicity and brain uptake [59, 147, 165, 208]. PET imaging of ß-adrenoceptors in human brain, the follow- Reduced lipophilicity results in little transport of the test ing questions should be answered in this review: drug across phospholipid bilayers, and increased lipophilicity promotes nonspecific binding of the compound to blood cells (1) Do other lipophilic ß-blockers exist which could be and plasma proteins, which reduces delivery to the brain. labeled with 11C or 18F and tested as radiopharmaceu- ticals for cerebral ß-adrenoceptor imaging? 3. Lack of Affinity to P-Glycoprotein (2) Can a strategy be devised to increase the brain uptake of Although successful CNS radioligands possess logP established ß-adrenoceptor ligands, so that they become values between +0.5 and +3, this does not imply that all suitable for visualisation of ß-adrenoceptors within the compounds with that lipophilicity will show good brain central nervous system? uptake. Many ß-blockers are substrates for P-glycoprotein (Pgp) [174]. This protein is expressed in endothelial cells of the blood-brain barrier and it promotes active efflux of drugs from the CNS. Cerebral uptake of Pgp-substrates is therefore 1 Calculated logP values were determined with the computer program Pallas. All values much lower than would be expected on the basis of their mentioned in this article refer to pH 7.40. lipophilicity [101]. 1522 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al.

4. Optimal Molecular Size and Charge 1. Can the brain uptake of radioligands be predicted on the basis of (measured or calculated) octanol/water partition Besides lipophilicity, the distribution of charge within a coefficients? molecule seems to affect its brain uptake. Higher uptake (0.8-4.8% ID/g) has been observed for compounds with 2. Can the magnitude of the specific binding (i.e., the electron withdrawing substituents in beta-position to the signal-to-noise ratio in PET images) of radioligands in amine group (pKa values 7.4 to 8.3) than for those with more target organs such as the brain be predicted on the basis basic amine groups (pKa values > 8.9, < 0.4% ID/g), even of their in vitro affinities to ß-adrenoceptors? though both classes of compounds had similar octanol/water To answer the first question, we plotted the uptake of partition coefficients at pH 7.4 [82]. sixteen ß-adrenoceptor ligands within rat CNS against their Passive diffusion across the blood-brain barrier is also (calculated) log P value at pH 7.4 (Fig. 1). This plot suggests dependent on molecular volume, larger volumes resulting in that optimal brain uptake of ß-blockers occurs at log P values reduced transport. It has been claimed that for optimal brain between +2 and +3, just as has been described for other uptake, a drug should have a molecular weight smaller than radiopharmaceuticals. Unfortunately, ß-blockers with log P 600 Da [69]. The criterion of molecular size is not relevant values > 3 have not yet been labeled with a positron emitter to ß-adrenoceptor imaging, since most ß-adrenoceptor (ant) and evaluated for PET imaging. Therefore, no data points are agonists have molecular weights between 200 and 350 Da. available for the right half of the parabola.The fitted curve (a Boltzmann sigmoidal) has a good correlation coefficient (r = 5. Specificity for the Target 0.97) and the relationship between log P and brain uptake is highly significant (p = 0.0003). However, two compounds The ideal radioligand should bind to a single receptor were not included in the fit since they did not obey the population only. Changes in binding parameters can then be general trend. In figure 1, these ligands are indicated by attributed to one clearly-defined subtype. Truly specific asterisks. compounds are rare. If the anatomic localization of receptor populations within the human brain is sufficiently distinct, a single ligand with affinity to all sites of interest can be employed. However, visualisation of the noradrenergic system requires highly specific ligands, since ß-adrenocep- tors are widely distributed throughout the brain and low densities are only observed in white matter, pons and medulla [257]. Most ß-adrenoceptor antagonists display significant affinity towards serotonin 5-HT1A, 5-HT1B and 5- HT1D receptors. Affinity of the radioligand to these serotonergic sites should be at least 2 (preferably even 3) orders of magnitude less than that to ß-adrenoceptors for successful PET imaging [198].

6. Resistance to Metabolism An ideal radioligand should either show negligible metabolism within a PET time scale (i.e., 2 h) or it should be metabolized to hydrophilic radioactive products with negli- gible brain uptake. In that case, bound radioactivity within Fig. (1). Relationship between (calculated) log P and brain the CNS will reflect mainly parent compound which greatly uptake of ß-adrenoceptor ligands. Brain uptake is plotted as the facilitates tracer-kinetic modeling. SUV in rat brain at 60 min post injection (with exception of formoterol and procaterol for which only data at 10 min post 7. Amenable to Labeling injection were available). Uptake data were from the following publications: CGP [241], PRO [245], FCG [241], PIN [63], FOR Candidate radiopharmaceuticals should possess molecular [246], BIS [215], ICYP [63], IPIN [236], CAR [65], FEC [67], FPR groups that can be labeled using rapid synthetic procedures. [234], BUP [63], FCA [240, 66], PEN [63], ICI [168], CVD [63]. Because of the short half-lives of positron emitters (11C only 20 minutes), this is a stringent requirement. The most noteworthy exception is 11C-carvedilol (CVD). This drug is quite lipophilic (calculated log P + 2.97 at pH PREDICTIVE VALUE OF THE CRITERIA 7.4), but its brain uptake is negligible (SUV £ 0.08 at 60 min The literature on ß-blockers usually provides only the post injection, [63]). The exceptionally low brain uptake is following information: (i) chemical structure of the com- probably due to the fact that carvedilol is a high-affinity pound; (ii) some proof of its action (affinity to ß-adrenocep- substrate for P-glycoprotein and actively expelled from the tors, or data on functional antagonism); (iii) in some cases, CNS, in contrast to other ß-blockers which are only weak substrates for this ATP-dependent drug efflux pump [174]. also a measured octanol/water partition coefficient. If 11 candidate radiopharmaceuticals should be selected based on Another exception is C-ICI 118,551 (ICI). Brain uptake of literature data, the following questions may arise: this compound is much higher than predicted on the basis of the curve fit. This finding is hard to explain - perhaps the PET Imaging of Beta-Adrenoceptors in Human Brain Current Pharmaceutical Design, 2004, Vol. 10, No. 13 1523 ligand is metabolized to a lipophilic radioactive product which can more easily cross the blood brain barrier. Unfortunately, the literature does not provide information on radiolabeled species arising from 11C-ICI 118,551. Figure 1 suggests that candidate radioligands should possess log P values greater than +1.5 in order to have adequate brain uptake. Apparently, octanol/water partition coefficients can predict uptake of ß-adrenoceptor (ant) agonists within the CNS, although there are a few (2 out of 16) exceptions to the general rule. To answer the question if the ß-adrenoceptor affinity of a ligand can predict the magnitude of its specific signal in PET images, we plotted the measured ratio of specific/nonspecific binding (signal-to-noise ratio) for various ß-blockers in rat heart in vivo against their binding potentials (B max divided by Kd determined in vitro, see Figure 2). A similar figure cannot be prepared for rat brain, since only four ß-adrenoceptor ligands (FEC, FCA, ICYP and IPIN) have shown specific Fig. (2). Relationship between the in vitro affinities of ß- binding within the CNS. To calculate B /K in rat heart, we adrenoceptor ligands and their target/nontarget ratios observed max d in rat heart in vivo. Target/nontarget ratios were calculated from assumed a Bmax of 6 pmol/g wet weight of tissue [137] and a ratio of the ß :ß subtypes of 83:17 [164]. tissue uptake in the absence and presence of propranolol, at 60 min 1 2 after injection (with exception of ICI118,551, bisoprolol and The data from eleven compounds were well fitted by a CGP20712A, for which only data at 30 min were available). Uptake hyperbola (r = 0.97, p < 0.0001). That the relationship data were from the following publications: ICI [168], PIN [63], BIS between in vitro affinity and target/non-target ratio in PET [215], FCG [241], CGP2 [73], FEC [67], CGP1 [242], CGP3 [241], imaging is curvilinear rather than linear is not surprising. FCA [66], CAR [65], ICYP [63], CVD [63]. Binding of potent ß-adrenoceptor antagonists approaches equilibrium slowly, i.e. true equilibrium is reached only after UNEXPLORED CANDIDATES several hours. It is thus possible that an interval of 60 min post injection is too short to acquire an optimal ratio of Are there still any ß-blockers with moderate lipophilicity specific/nonspecific binding for potent radioligands, such as (log P +1.5-3) and high affinity which could be labeled with -10 CAR and ICYP. Moreover, if Kd is very small (<= 10 M), a positron emitter? In order to answer this question, we the expression B/Kd in the Scatchard equation will no longer performed an extensive literature search and classified ß- be negligible, especially in the case of ligands labeled with adrenoceptor antagonists into four different groups: (i) carbon-11. Target-nontarget ratios (B/F) will in such cases Extremely potent compounds (Kd < 1 nM, Table 1), (ii) be smaller than Bmax/Kd . Potent compounds (Kd 1-10 nM, Table 2), (iii) Beta-blockers with moderate affinities (K 10-100 nM, Table 3) and (iv) Apparently, values for radioligand affinity determined d in Weak ß-adrenoceptor antagonists (K > 100 nM, Table 3). vitro can be used to predict the results of myocardial d imaging. However, one compound deviated from the general Of the 57 extremely potent ß-blockers listed in Table 1, pattern shown in Fig. 2, [11C]carvedilol (CVD). According to only 10 are sufficiently lipophilic: bucindolol, carvedilol, in vitro assays, Bmax/Kd-1 of S-carvedilol in rat heart is 11.5 CGP20712A, exaprolol, fluorocarazolol, fluoroethylcara- to 14 [175], but 11C-carvedilol did not show any specific zolol, iodoazidobenzylpindolol, iodohydroxybenzylpindolol, binding in rat heart in vivo [63]. The reason for the failure of L643,717, and compound 21a. Carvedilol and CGP20712A [11C]carvedilol as a myocardial imaging agent is not clear. have already been labeled and found to be unsuitable for The affinity of carvedilol to ß-adrenoceptors may have been cerebral ß-adrenoceptor imaging [63, 242]. Fluorocarazolol overestimated. Estimations of the affinity of ß-adrenoceptor and fluoroethylcarazolol are successful ligands, but they antagonists can vary by a factor of 10, depending on the cannot be employed for human studies because of a positive tissue preparation and the laboratory of assay. The affinity of Ames test [62]. Iodoazidobenzylpindolol is a photoaffinity carvedilol was determined in guinea pig atrium rather than label which cannot be used for PET imaging. [125I]Iodo- rat ventricle. If there is a species difference between rat and hydroxybenzylpindolol shows very poor target/nontarget guinea pig and if the affinity of carvedilol was indeed ratios in vivo [35]. Radioactive bucindolol, exaprolol, L643, overestimated, carvedilol data may in fact fit the plotted 717, and compound 21a have not yet been prepared (see curve. Figure 3 and [105] for chemical structures). Unfortunately, bucindolol and compound 21a are not amenable to labeling Figure 2 suggests that for an acceptable signal-to-noise with a positron emitter. However, exaprolol can be labeled ratio, the binding potential (Bmax/Kd based on in vitro assays 11 of B and K ) of a radiolabeled ß-blocker should be greater by reaction of a desisopropyl precursor with C-acetone, and max d L643,717 by reaction of a hydroxy precursor with 11C- than 10. Based on the data presented in Fig. 1 and 2, we may predict that ligand candidates should have (calculated) log P methyl iodide. values > +1.5 and affinities < 1.5 nM for successful ß- Analogs of pindolol (not listed in Table 1) may show adrenoceptor imaging. high affinities to ß-adrenoceptors and could be explored for 1524 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al.

Table 1. ß-Adrenoceptor Antagonists with Affinities in the sub-nM Range for at least one of the ß-Adrenoceptor Subtypes

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

(-) Alprenolol Not determined 0.6 [58] +0.35c +0.80m [5]

AlpM Not determined 0.2 [181] -1.77c -1.58c (2 isomers)

Arotinolol 0.2 [237] 0.5 [237] -0.34c

(-) Befunolol 1 [133] 0.9 [133] -0.62c -0.12m [192]

BFE61 Not determined 0.2 [228] -0.11c

Bucindolol 1.7 [31] 0.8 [31] + 1.66c

Bucumolol 0.8 [112] Not determined -0.60c +0.93m [112]

Bunitrolol 0.7 [158] Not determined -0.92c -0.36m [192]

(-) Bupranolol 1.6 [143] 0.3 [143] +0.29c +0.57m [141]

Butylpindolol 0.7 [45] 0.7 [45] -0.16m [45]

Carazolol 0.15 [117] Not determined +0.80c +1.36m [220]

(-) Carteolol 0.1 [133] 0.1 [133] -1.55c

(-) Carvedilol 0.4 [175] Not determined +2.97c

CGP 12177 0.3 [173] 0.9 [173] -2.07c -0.49m [5]

CGP 12388 Like CGP 12177 [241] Like CGP 12177 [241] -2.01c

(-) CGP 20712A 0.5 [61] 4200 [61] +1.78c

Chloranolol Sub-nM [78] Not determined +0.47c

(-) Dihydroalprenolol 0.6 [58] 0.4 [58] +0.69c +1.00m [220]

Erhardt et al., compd 12 0.1 [77] 0.5 [77] -1.19c

Erhardt et al., compd 14 0.2 [77] 1 [77] -1.25c

Exaprolol 0.2 [110] Not determined +1.61c

Fluorocarazolol 0.4 [243] 0.1 [243] +2.19c

Fluoroethylcarazolol 0.5 [67] 0.4 [67] +1.66c

ICI 89,406 0.3 [180] 100 [180] -1.05c

ICI 118,551 68 [25] 0.5 [25] +1.07c +1.33m [45]

ICI 147,798 0.8 [126] 1.6 [126] -0.11c

Indenolol Like propranolol [229] Not determined -0.05c

Iodoazidobenzylpindolol Unknown 0.5-0.7 [191] +4.16c

Iodocyanopindolol < 0.1 [33] < 0.01 [90] +0.43c +1.26m [220]

Iodohydroxybenzylpindolol < 0.2 [238] 0.2 [153] +2.68c

Iodopindolol 0.2 [146] Not determined +0.62c

IPS 339 13 [155] 0.8 [155] +0.98c

K 105 Like bupranolol [144] Like bupranolol [144] -0.24c

Kierstead et al., compd 4a 35 [129] 0.6 [129] -2.80c

Kierstead et al., compd 4d 650 [129] < 0.1 [129] -3.71c

Kierstead et al., compd 4f 60 [129] 0.8 [129] -3.38c

Kierstead et al., compd 4v 55 [129] < 0.1 [129] -3.52c PET Imaging of Beta-Adrenoceptors in Human Brain Current Pharmaceutical Design, 2004, Vol. 10, No. 13 1525

(Table 1) contd….

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Kö-1313 < propranolol [18] 22 [114] -0.83c

Kö-1366 < propranolol [18] Like propranolol [18] -0.92c

L 643,717 0.8 [169] 7413 [169] +3.36c

Los Angeles, compd 21a 182 [150] 0.3 [150] +3.76c

LT 18-502 0.7 [108] 0.4 [108] -0.29c

Mauléon et al., compd 3b 0.2 [156] < 0.1 [156] +0.91c

McClure et al., compd 34 0.6 [158] Not determined +0.14c

McClure et al., compd 40 0.7 [158] Not determined +0.86c

McClure et al., compd 42 0.7 [158] Not determined +0.86c

(S,R) Nipradilol 0.3 [211] 0.7 [211] -0.75c

(-) Penbutolol < propranolol [99] Not determined +1.17c +1.97m [192]

(-) Pindolol 0.9 [106] 1.2 [106] -0.53c -0.33m [45]

Procinolol < alprenolol [214] Not determined +0.84m [192]

(-) Propranolol 0.6 [58] 0.7 [58] +0.43 +1.20m [45]

Soquinolol 3.3 [92] 0.8 [92] -1.78c

Spirendalol 12 [169] < 0.1 [169] +0.67c

Tertatolol 0.4 [244] 1.5 [244] -0.09c

(-) Timolol 0.8 [58] 0.5 [58] -2.14c

Toliprolol Like bupranolol [254] 44 [114] -0.22c

Symbols: compd = compound; c = calculated, m = measured log P.

Table 2. ß-Adrenoceptor Antagonists with Affinities in the nM Range for at least one of the ß-Adrenoceptor Subtypes

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Adimolol 1.2 [151] Not determined +1.87c

BFE37 Not determined 2.3 [228] +0.56c

Bisoprolol 1.6 [128] 100 [128] -0.20c

BL 343 Ac 3.2 [131] Not determined -0.51c

Bopindolol 229 [108] 4.3 [108] +2.45c

Bufetolol 2.2 [118] Not determined -0.53c

Bufuralol 2.5 [166] Not determined +0.73c

Bunolol See levobunolol See levobunolol -0.53c

Capsinolol 6.9 [40] 9.1 [40] +1.50c

Carré et al., compd 15a Unknown 1.3 [37] +0.04c

Carré et al., compd 15b Unknown 1.3 [37] +0.13c

Carré et al., compd 9b Unknown 2.0 [37] +1.41c

Compound A Like MK-761 [207] Like MK-761 [207] +0.23c 1526 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al.

(Table 2) contd….

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Compound 10 6.8 [28] 2.1 [28] -0.53c

Dilevalol 6.3 [166] Not determined +0.65c

Epanolol 3.8 [24] 468 [24] -0.75c +0.92m [24]

Eugenolol 5.2 [253] 6.6 [253] +0.29c

Falintolol 23 [28] 6.9 [28] -0.86c

Ferulidilol 9.1 [253] 31 [253] +2.21c

Flestolol 9.8 [89] 6.9 [89] -0.93c

Flusoxolol >= pindolol [157] Not determined +1.19c

HX-CH 44 BS 5-10 [50] 7493-10000 [50] -4.21c

Kam 96 2.5 [124] 6.3 [124] -0.32c

Labetalol 4.9 [44] 7.9 [44] +0.65c

Levobunolol Not determined 2.1 [187] -0.53c

LK 203-939 4.5 [163] 9332 [163] -0.55c

LK 204-545 3.2 [163] 10965 [163] +0.81c

LL 21-945 2.5 [43] Not determined Unknown

(-) Medroxalol 4 [41] Not determined +0.50c

Mepindolol 1.6 [10] 5 [10] -0.39c +0.05m [192]

Metipranolol 5 [223] 4 [223] +0.08c +0.43m [192]

MK 761 1.5 [169] Not determined -1.78c

l-Moprolol 1.2 [183] 5.8 [183] -0.77c -0.64m [192]

Nebivolol 7.6 [31] 310 [31] +2.22c

Oxprenolol 2.1 [106] 6.2 [106] -0.18c

(-) P0160 3 [87] 340 [87] Unknown

S 2395.1 1259 [68] 4 [68] Unknown

Sulfinalol As MK761 [226] Not determined -0.30c

Tilisolol 55 [172] 2.8 [172] -2.00c

(-) Tolamolol 2.8 [2] 36 [2] +0.81c

Xibenolol 2.9 [106] 1.7 [106] +0.19c

Abbreviations as in Table 1

Table 3. Low-Affinity ß-Blockers

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Affinity 10-100 nM

(-) Amosulalol 13 [60] Not determined +0.55c

9-Amino-Acridine Propranolol 20 [160] 30 [46] +1.72c

(-) Betaxolol 19 [142] 151 [142] +0.24c +0.55m [192] PET Imaging of Beta-Adrenoceptors in Human Brain Current Pharmaceutical Design, 2004, Vol. 10, No. 13 1527

(Table 3) contd….

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Affinity 10-100 nM

Bevantolol 15 [230] 589 [230] +2.22c

BFE-55 Not determined 20 [228] -0.11c

exo Bornaprolol 25 [138] Not determined +1.44c +2.53m [192]

Cetamolol 20 [195] 50 [195] -1.93c -1.03m [192]

Cicloprolol 15 [213] Not determined -0.15c

Dehydrozingeronolol 31 [253] 141 [253] -0.52c

Eugenodilol 13 [253] 47 [253] +2.44c

H-I 42 BS 14 [49] 3000 [49] -0.76c

Isoeugenolol 13 [148] 759 [148] +0.32c

LK 203-030 17 [163] 16596 [163] -1.09c

LK 204-155 28 [163] 60256 [163] -0.02c

Nadolol 13 [68] 32 [68] +1.29c

Nadoxolol Moderate [250] Not determined +1.85c

Pafenolol 28 [71] 2240 [71] -0.69c +0.30m [193]

Pamatolol 28 [120] 2884 [120] -1.05c

Pargolol Moderate [111] Not determined -0.19m [192]

Primidolol Moderate [201] Not determined Unknown

Prizidolol 69 [233] 93 [233] -1.14c

Talinolol Moderate [53, 79] Not determined -0.12c

Trimetoquinol 324 [150] 44 [150] +1.44c

Vanidilol 21 [253] 22 [253] -1.12c

Vanidipinedilol 81 [255] 229 [255] Unknown

Vaninolol 21 [253] 174 [253] -0.65c

Vasomolol 39 [253] 1549 [253] -0.23c

Xamoterol 56 [152] 5754 [152] -2.73c

Zingeronolol 30 [252] 155 [252] -0.64c

Affinity > 100 nM

Acebutolol 646 [142] 4169 [142] -0.77c

(-) Atenolol 603 [142] 4266 [142] -2.07c -2.24m [142]

Butidrine Like atenolol [27] Like atenolol [27] +1.11c

Butofilolol Like atenolol [140] Like atenolol [140] +0.11c

Butoxamine 15136 [204] 3715 [204] -0.64c

Celiprolol 350 [97] 2800 [97] -1.13c

DAPN 300 [46] Not determined ?

Esmolol 110 [194] 4677 [194] -0.44c

Ferulinolol 103 [253] 2412 [253] -0.13c 1528 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al.

(Table 3) contd….

Compound ß1 affinity (nM) ß2 affinity (nM) Log P (pH 7.4)

Affinity > 100 nM

Landiolol 257 [113] 66069 [113] -2.11c

LT 20-785 1175 [108] 214 [108] -1.92c

(-) Metoprolol 141 [142] 631 [142] -0.56c

Nifenalol 126 [216] Not determined -0.59c

(-) Practolol 1175 [142] 128825 [142] -1.74c -1.49m [106]

Pronethalol Not determined 160 [115] -0.10c

Sotalol 603 [106] 148 [106] -1.15c

Xanthonolol 50000 [39] Not determined +2.15c

Abbreviations as in Table 1

NH N O OH CN NH S OH NH O HN

Bucindolol L643, 717 OCH3 I OCH3

I HN O HO NH OH

HO Exaprolol Los Angeles 21a

Fig. (3). Chemical structures of some potent ß-blockers which have not yet been labeled with a positron emitter. imaging purposes. These include: benzylcyanopindolol, result was to be expected, since for these antagonists, Bmax/ butylcyanopindolol, cyanopindolol, cyclohexylcyanopindolol, Kd < < 1. Therefore, they cannot accumulate in target tissues ethylesterpindolol, iodoallyl-cyanopindolol, iodobutylcyano- above plasma levels due to ligand-receptor interaction. pindolol, iodocyclohexylcyanopindolol, iodoethylesterpin- Thus, extensive screening of the pharmacological litera- dolol, and isopropylcyanopindolol [105]. However, we do ture yields very few novel drugs which can still be labeled not expect these compounds to be suitable for cerebral beta- with a positron emitter and be evaluated as radiopharma- adrenoceptor imaging as: (i) they are not very lipophilic 11 ceuticals for cerebral ß-adrenoceptor imaging. C-Exaprolol (calculated log P values < + 1.5 with exception of iodocyclo- 11 and C-L643,717 may be prepared, using the acetone and hexylcyanopindolol), so they will probably have low brain methyliodide methods. uptake and (ii) they probably bind not only to ß-adrenocep- tors but also to 5-HT and 5-HT receptors within mamma- 1A 1B ENHANCING LIGAND UPTAKE: BLOOD-BRAIN lian brain [63]. BARRIER OPENING Of the 41 potent compounds listed in Table 2, only one Since there are very few novel candidate ligands for ß- has a K < 1.5 nM and a log P > +1.5, namely adimolol. d adrenoceptor imaging in the CNS, we considered the possi- Unfortunately, adimolol has a chemical structure which is not amenable to labeling with either 11C or 18F. bility of enhancing the brain uptake of existing radioligands (e.g. 11C-CGP 12388 or 11C-CGP12177) by temporary Although some of the 46 ß-blockers listed in Table 3 opening of the blood-brain barrier. Various strategies for have been labeled with 11C or 18F and evaluated for imaging BBB opening have been proposed to deliver therapeutic purposes, no specific binding was ever observed in vivo. This agents (cytostatic drugs, antisense oligonucleotides, immune PET Imaging of Beta-Adrenoceptors in Human Brain Current Pharmaceutical Design, 2004, Vol. 10, No. 13 1529 proteins and growth factors) to human brain for the treatment Although such strategies have shown to be effective and of intracerebral tumors and other diseases [107, 190, 134]. will certainly result in increased uptake of polar radiophar- Permeability of the BBB can be increased by the maceuticals within the CNS [6, 7, 119], they cannot be used following techniques: for cerebral ß-adrenoceptor imaging. First, the barrier modifiers have to be infused through a Osmotic Shock vessel which supplies blood to the brain, preferably the arteria carotis. Intrafemoral infusion is not effective [34]. After If a hypertonic solution of mannitol, arabinose or urea is infusion of the therapeutic agents, the blood-brain barrier is administered for 30 s through a vessel which supplies blood opened in one cerebral hemisphere only (the ipsilateral to the brain, the endothelial cells in the cerebral vessels hemisphere). Cannulation of the carotis followed by osmotic contract, both via passive shrinking and because of calcium- opening of the blood-brain barrier is a surgical manipulation induced contraction of the cytoskeleton. This leads to which cannot be performed in healthy volunteers. It requires transient opening of the blood-brain barrier, for a period of general anesthesia [203] and is only allowed in patients when 10 min to about 2 h [22, 134, 212, 248]. the benefits of the treatment outweigh its risks. Receptor-Mediated Permeability Increase Second, osmotic opening of the blood-brain barrier app- ears to be relatively dangerous. Development of microinfarc- The cytoskeleton of endothelial cells can also be forced tion is possible [225], although this risk can be minimized by to contract by administration of bradykinin or histamine H2 R administration of the mannitol solution via a Millipore filter receptor agonists. The synthetic peptide RMP-7 (Cereport , to prevent infusion of microcrystals [235, 189]. Seizures labradimil) is used for this purpose in clinical trials [17, 57, were noticed in 2 out of 45 cancer patients upon infusion of 74]. mannitol [197]. Finally, there is the possibility of subsequent demyelination and development of multiple sclerosis [3]. Inducing Endothelial Leakiness This combination of factors makes opening of the BBB a The endothelium lining the cerebral blood vessels can be last resort for the treatment of cancer, but not a viable option made leaky by transient infusion of various compounds, such for the study of neuroreceptors within the human CNS. as short-chain alkylglycerols, sodium dodecylsulfate, dehyd- rocholate and oleic acid. Such compounds induce large pores ENHANCING LIGAND UPTAKE: PRODRUG in the vessel wall which allow the transport of therapeutic APPROACH drugs with molecular weights up to 70 kD [76, 176, 199, 219, 227]. Another approach to enhance the brain uptake of established radioligands is esterification of the OH-group in Acute Acidosis the aryloxy part of the molecule, resulting in a lipophilic prodrug which can be converted to the active compound by Infusion of an acidic buffer (40 mM malonic acid pH 2.5) cerebral esterases. An example of this targeting strategy is induces transient (60 s) opening of the tight junctions in the the registered drug bopindolol (SandonormR, see Fig. 4). cerebral endothelium, resulting in significant brain uptake of Bopindolol is the benzoyl ester of the beta-blocker LT18- polar test substances [178]. A similar effect is observed after 502. The active drug (LT18-502) has a high affinity to the ß1 provoking acute hypertension by infusion of epinephrine or and ß2 subtypes of adrenoceptors (Kd 0.7 and 0.4 nM), but its phenylephrine [171]. lipophilicity is low (calculated logP -0.29 at pH 7.4) which results in a relatively low bioavailability after oral dosing. Infusion of Bacterial Glycopeptides The prodrug (bopindolol) is much more lipophilic (calcu- Causes a time- and dose-dependent increase of the lated logP +2.45 at pH 7.4) and easily taken up from the permeability of the blood-brain barrier for substances with intestine. In contrast to its active metabolite, bopindolol has a molecular weight smaller than 20 kD [218]. rather low affinity to ß1-adrenoceptors (Kd 229 nM), but it is

NH NH Esterases O O

O NH HO NH OH O O

Bopindolol LT18-502

Fig. (4). Conversion of bopindolol to its active metabolite by esterases. 1530 Current Pharmaceutical Design, 2004, Vol. 10, No. 13 Waarde et al. rapidly converted to LT18-502 in vivo, since the benzoyl ICYP = Iodocyanopindolol ester bond is hydrolyzed [30, 42, 108, 109, 177, 200]. IPIN = Iodopindolol A similar targeting strategy could be employed to increase PEN = Penbutolol the delivery of hydrophilic ligands to the brain of intact animals or man. A calculated logP of +2.45 (as displayed by PIN = Pindolol bopindolol) is about optimal for passive diffusion of a PRO = Procaterol radiolabeled compound across the blood-brain barrier upon intravenous injection [147, 59, 165, 208]. Hopefully, the SUV = Standardized Uptake Value benzoyl esters are not substrates for P-glycoprotein, for this would result in very low brain uptake, as was observed for REFERENCES 11 C-carvedilol. 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